Authors
Zheng Zhang, Yong-Sheng Yang, Meng-Ting Xu, Rong Duan, Ji-Xin Jiang, Rong-Tao Li, Rui-Rong Ye
Published in
Dalton transactions (Cambridge, England : 2003). Nov 04, 2026. Epub Nov 04, 2026.
Abstract
In this work, six multifunctional cyclometalated iridium(III) complexes Ir-CA-1-3 and Ir-GFB-1-3 were designed and synthesized by introducing peroxisome proliferator-activated receptor alpha (PPARα) agonists clofibrate (CA) and gemfibrozil (GFB) as derivative fragments. Their in vitro antitumor activity was systematically evaluated, and the results revealed that Ir-CA-1-3 and Ir-GFB-1-3 exhibited better anti-tumor activity than cisplatin. Among these compounds, Ir-CA-1 and Ir-GFB-1, which have the strongest anti-proliferative activity, were selected as representatives to evaluate their anti-tumor activity. Mechanistic studies revealed that Ir-CA-1 and Ir-GFB-1 could activate PPARα while inducing mitochondrial dysfunction, accompanied by a decrease in mitochondrial membrane potential (MMP) and excessive production of reactive oxygen species (ROS). Mitochondrial dysfunction triggered the intrinsic apoptotic pathway, as evidenced by the decreased Bcl-2 expression, increased Bax expression, and activation of caspase-3 induced by Ir-CA-1 and Ir-GFB-1. Moreover, Ir-CA-1 and Ir-GFB-1 exerted multimodal antitumor effects by triggering gasdermin E (GSDME)-mediated pyroptosis, which in turn induced immunogenic cell death (ICD), as evidenced by the release of lactate dehydrogenase (LDH) and ATP, as well as high mobility group box 1 protein (HMGB1) secretion and calreticulin (CRT) externalization. In addition, Ir-CA-1 and Ir-GFB-1 effectively suppressed the proliferation, colony formation, and migration of tumor cells in concentration- and time-dependent manners.
PMID:
42980385
Bibliographic data and abstract were imported from PubMed on 04 Nov 2026.
Read full publication at:
Please sign in
to see all details.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 14
- Comments 0